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    N-(5-((ARYL OR HETEROARYL)METHYLOXY)PENTYL)-SUBSTITUTED IMINOSUGARS AS INHIBITORS OF GLUCOSYLCERAMIDE SYNTHASE
    3.
    发明公开
    N-(5-((ARYL OR HETEROARYL)METHYLOXY)PENTYL)-SUBSTITUTED IMINOSUGARS AS INHIBITORS OF GLUCOSYLCERAMIDE SYNTHASE 审中-公开
    N-（5 - （（ARYL-ODER HETEROARYL）METHYLOXY）PENTYL）-SUBSTITUIERTE IMINOZUCKER ALS INHIBITOREN DER GLUCOSYLCERAMIDSYNTHASE

    公开(公告)号：EP3122726A1

    公开(公告)日：2017-02-01

    申请号：EP15719845.8

    申请日：2015-03-23

    申请人： Academisch Medisch Centrum ,  Universiteit Leiden

    发明人： OVERKLEEFT, Herman Steven ,  VAN BOECKEL, Stan ,  AERTS, Johannes Maria Franciscus Gerardus ,  GHISAIDOOBE, Amar ,  VAN DEN BERG, Richard

    IPC分类号： C07D211/46 ,  C07D401/12 ,  C07D405/12 ,  A61K31/445 ,  A61K31/4545 ,  A61P3/00 ,  A61P25/16 ,  A61P9/10

    CPC分类号： C07D211/40 ,  C07D211/46 ,  C07D401/12 ,  C07D405/12

    摘要： Deoxynojirimycin and deoxygalactonojirimycin derivatives according to the present invention are N-alkylated D-galacto, D-gluco- or L-ido-deoxynojirimycin with a linear methyloxypentyl group bearing various sidegroups and a non-fused bicyclic aromatic group (“X”) on the methyloxy-carbon. These compounds display an increased inhibitory potency towards GCS, and/or an increased inhibitory potency towards GBA2, and/or a decreased inhibitory potency towards GBA1, relative to known deoxynojirimycin derivatives of the same (D-gluco, L-ido or D-galacto) configuration. Therefore, compounds of the present invention are effective in the treatment of diseases which are associated with an irregular level of cytosolic or lysosomal glucosylceramide and/or higher glycosphingolipids, such as a lysosomal storage disorder, such as Gaucher disease, Fabry disease, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, Sialidosis, Niemann Pick disease type C and AMRF, or a symptom of one of the diseases collectively classed as metabolic syndrome, such as obesity, insulin resistance, hyperlipidemia, hypercholesterolemia, polycystic kidney disease, type II diabetes and chronic inflammation, or a neurodenegerative disorder, such as Parkinson disease or Lewy-body dementia.

    摘要翻译： 根据本发明的脱氧野尻霉素和脱氧半乳糖吉非霉素衍生物是N-烷基化D-半乳糖，D-葡萄糖或L-异 - 脱氧野尻霉素，其具有带有各种侧基的直链甲氧基戊基和非稠合双环芳族基团（“X”） 甲氧基 - 碳。 式（I），式（Ia）。 相对于已知的相同的脱氧野尻霉素衍生物（D-gluco，L-ido或D-半乳糖），这些化合物显示增加的对GCS的抑制效力和/或增加对GBA2的抑制效力和/或降低对GBA1的抑制效力 ）配置。 因此，本发明的化合物可有效治疗与不稳定水平的细胞溶质或溶酶体葡萄糖神经酰胺和/或更高的糖鞘脂相关的疾病，例如溶酶体储存障碍，例如戈谢病，法布里病，泰麻 疾病，Sandhoff病，GM1神经节苷脂病，Sialidosis，Niemann Pick疾病C型和AMRF，或统称为代谢综合征的疾病之一的症状，如肥胖，胰岛素抵抗，高脂血症，高胆固醇血症，多囊肾病，II型糖尿病 和慢性炎症，或神经退行性疾病，如帕金森病或路易体痴呆。

    IMPROVED TREATMENT OF CYSTIC FIBROSIS
    5.
    发明授权
    IMPROVED TREATMENT OF CYSTIC FIBROSIS 有权
    改进的方法治疗囊性纤维化

    公开(公告)号：EP2010551B1

    公开(公告)日：2010-09-01

    申请号：EP07747401.3

    申请日：2007-04-24

    申请人： Academisch Medisch Centrum

    发明人： AERTS, Johannes Maria Franciscus Gerardus ,  BOOT, Rolf Gabriel

    IPC分类号： C07H15/12 ,  A61K31/70 ,  A61P43/00

    CPC分类号： A61K31/70

    摘要： The present invention discloses a therapeutic target for the treatment of cyst ic fibrosis. It was found that inhibition of non-lysosomal glucosylceramidase (GBA2) sufficiently restores chloride current in cells from CF patients carrying the common delF508-CFTR mutation. With the catalytic centre (4) of the enzyme positioned on top of the membrane bilayer face particularly potent inhibitors are found in deoxynojirimycin derivatives having a group that is capable of inserting in the membrane bilayer.

    IMPROVED TREATMENT OF CYSTIC FIBROSIS
    7.
    发明公开
    IMPROVED TREATMENT OF CYSTIC FIBROSIS 有权
    改进的方法治疗囊性纤维化

    公开(公告)号：EP2010551A1

    公开(公告)日：2009-01-07

    申请号：EP07747401.3

    申请日：2007-04-24

    申请人： Academisch Medisch Centrum

    发明人： AERTS, Johannes Maria Franciscus Gerardus ,  BOOT, Rolf Gabriel

    IPC分类号： C07H15/12 ,  A61K31/70 ,  A61P43/00

    CPC分类号： A61K31/70

    摘要： The present invention discloses a therapeutic target for the treatment of cyst ic fibrosis. It was found that inhibition of non-lysosomal glucosylceramidase (GBA2) sufficiently restores chloride current in cells from CF patients carrying the common delF508-CFTR mutation. With the catalytic centre (4) of the enzyme positioned on top of the membrane bilayer face particularly potent inhibitors are found in deoxynojirimycin derivatives having a group that is capable of inserting in the membrane bilayer.

    GLYCOSYLATED METABOLITES
    8.
    发明公开
    GLYCOSYLATED METABOLITES 审中-公开
    糖基化代谢物

    公开(公告)号：EP3314009A2

    公开(公告)日：2018-05-02

    申请号：EP16751025.4

    申请日：2016-06-24

    申请人： Universiteit Leiden

    发明人： AERTS, Johannes Maria Franciscus Gerardus ,  OVERKLEEFT, Hermen Steven

    IPC分类号： C12Q1/48 ,  G01N33/92 ,  G01N33/68

    CPC分类号： G01N33/92 ,  C12Q1/48 ,  G01N33/6893 ,  G01N2560/00

    摘要： The invention provides means and methods for detecting a glycosylated metabolite in a sample comprising adding to the sample a compound comprising a labelled glycosyl group coupled via an O-glycosidic bond to an aglycon with a specific structural formula wherein the glycosyl group comprises at least one isotope and/or a side chain being a label for detection, and wherein the sample is screened for the presence of a glycosylated metabolite with the glycosyl group other than a glucosylceramide. The invention further provides a method of treating a disorder caused by accumulation of a glycosylated metabolite other than glucosylceramide in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a glucosylceramide synthase (GCS) inhibitor.